Doxorubicin is a cytotoxic anthracycline antibiotic used as a first-line chemotherapeutic agent in treatment of various neoplastic conditions like lymphoblastic leukemia, myoblastic leukemia, breast and ovarian carcinoma etc. Despite the wide use of Doxorubicin, cardiotoxicity side effect remains a major concern. The mechanism of Doxorubicin induced cardiotoxicity is associated with impaired Ca2+ handling in the sarcoplasmic reticulum (SR) reducing the cardiac function. Sarcoplasmic reticulum Ca2+-ATPase 2 (SERCA2) is a major Ca2+ transport protein in the SR.
Arai et. al. (2000), has demonstrated that expression of mRNA encoding SERCA2 and the ability of the SERCA2 protein to take up Ca2+ were markedly decreased in Doxorubicin treated heart. This reduction in intracellular Ca2+ leads to reduction in heart rate due to reduced excitability of pacemaker cells in the sinoatrial node and other cells in the cardiac conduction system. Doxorubicin treatment induces a progressive and severe deterioration of the repolariztion phase in the ECG. This is indicated by an increased ST interval. A prolonged QT interval indicates ventricular tachyarrhythmias and a risk factor for sudden death. Administration of Doxorubicin also increases oxidative stress in the heart. Histopathological changes in doxorubicin treatment causes extensive vacuolization in the cytoplasm of myocardial cells, doxorubicin induced cardiac damage and marked edema, disorganized myocardial fibers, and necrosis.
Cardiotoxicity is a major side effect not limited to Doxorubicin. Isoproterenol is a non-selective beta-agonist used in treating heart block or bradycardia. The positive inotropic effect of isoproterenol is useful in increasing the strength of muscular contraction however it has associated cardiotoxic side effects namely tachycardia or elevated heart rate, cardiac dysrhythmias, increased risk of myocardial infarction and death due to cardiac arrest.
Digitalis another positive inotropic agent used in treatment of atrial fibrillation, flutter and congestive heart failure also has dose dependent toxicity. At high doses, digitalis induces irregular heartbeat, ectopic atrial tachycardia and cardiac arrest. The side effects of this drug greatly outweigh its therapeutic efficacy.
Cardiac dysfunction induced by drug substances result in conditions namely arrhythmias, atrial fibrillation, tachycardia or bradycardia etc which subsequently results in heart failure. Prevention of cardiac dysfunction by protecting the heart from toxic side effects of will greatly enhance the efficacy of these drug substances.
Apart from drug induced cardiac dysfunction, insults to the heart caused by lifestyle and disease conditions like stenosis, hypertension, atherosclerosis, myocardial infarction, ischemic heart disease, cardiomyopathy etc., also result in reduced cardiac function. This is due to an increased peripheral resistance which in turn increases the pressure load on the heart. Takizawa et. al. (1999), has reported that under these conditions of pressure-overload there is a reduction in transcription of SERCA2 mRNA expression which decreases SERCA2 protein concentration and decreases Ca2+ uptake in the SR.
Garcinol is a polyisoprenylated benzophenone derivative present in the fruit rinds of Garcinia species namely Garcinia indica (common name ‘Kokum’) and Garcinia cambogia (common name ‘Gombogee’) at 2-3% by weight. Literature reports extraction of Garcinol from Garcinia indica using aqueous organic solvents (Krishnamurthy et al., 1981) with a yield ranging from 0.8-1.5% and assay purity of only 50-70%. Garcinol is a yellow solid substance with a molecular weight of 602.8 and molecular formula C38H50O6.